Derivatives of benzamidine, the method of production thereof, pharmaceutical composition, its preparation and drug

 

The invention relates to a derivative of benzamidine formula I, where R1denotes-C(=NH)-NH2; R2denotes H; R3refers to -[C(R5)2]m-R5, R3and X together represent well-CO-N-, form a 5-membered ring, with R3refers to - C = O, and X denotes N, R4means And, cycloalkyl, -[C(R5)2]mAr; X represents O, NR5or CH2Y represents O, NR5N[C(R5)2]m-Ar, N[C(R5)2]m-Het, - N[C(R5)2]m-R5W represents a bond, -SO2-, -CO - or-NR5-. The compounds are inhibitors of coagulation factor (FGC) Ha and can be used for prophylaxis and therapy of thromboembolic diseases. Also described is a method of obtaining compounds, pharmaceutical composition and a drug. 5 S. and 2 C.p. f-crystals, 1 PL.

Description text in facsimile form (see graphic part). TM

Claims

1. Derivatives of benzamidine formula Iwhere R1denotes-C(= NH)-NH2; R2denotes H; R33refers to-C= O, and X denotes N, R4means And, cycloalkyl, -[C(R5)2]mAG; R5denotes H, a or benzyl, X represents O, NR5or CH2,
Y represents O, NR5N[C(R5)2]m-Ar, N[C(R5)2]m-Het, - N[C(R5)2]m-COOR5,



W represents a bond, -SO2-, -CO -, or-CONR5-,
And denotes alkyl with 1-20 C-atoms, where one or two CH2-groups can be replaced by O - or S-atoms or-CR5= CR5groups and/or 1-7 H atoms may be replaced by F,
AG represents naphthyl or phenyl, unsubstituted or one-, two - or tizamidine groups R1And, Ah', OR5or halogen;
AG' represents phenyl;
Het is a monocyclic unsaturated heterocyclic ring system containing one or two identical or different heteroatoms, such as nitrogen, oxygen and sulfur, which is unsubstituted or one - or polyamidine halogen or the group;
Hal denotes F, C1, Br or I,
m denotes 0, 1, 2, 3 or 4 and
n denotes 0, 1 or 2, 1-[2-(3,4-acid), acylamino-3-[4-(5-methyl-[1,2,4] oxadiazol-3-yl)phenoxy] propan-2-ol,
1-[4-(2-methoxyphenyl)piperazine-1-yl] -3-[4-(5-methyl-[1,2,4] oxadiazol-3-yl)phenoxy] propan-2-ol.

2. Connection on p. 1
and) 4-{ 3-[4-(2,6-dichloro-4-methoxybenzenesulfonyl)piperazine-1-yl] -2-hydroxypropylamino} benzamide;
b) 4-{ 3-[(4-isopropylbenzenesulfonyl)methylamino] -2-hydroxypropylamino} benzamide;
in) 4-{ 3-[4-(1-nativisation)piperazine-1-yl] -2-hydroxypropylamino} benzamide;
g) 3-(4-amidinophenoxy)-5-[(3-amidinophenoxy)methyl] oxazolidin-2-it,
and also their salts.

3. The method of obtaining derivatives of benzamidine formula I under item 1, and their salts, which consists in the fact that their release from their functional derivatives by treatment with an agent of the solvolysis or hydrogenolysis, with amedieval group release of her oxadiazoles derived by hydrogenolysis, and/or a base or acid of the formula I transferred to one of their salts.

4. A method of obtaining a pharmaceutical composition intended for use as an inhibitor of coagulation factor XA, characterized in that the compounds of formula I under item 1 and/or one of its physiologically acceptable salts together with at least animirovannyy form.

5. The pharmaceutical composition intended for use as an inhibitor of coagulation factor XA, characterized in that it contains at least one compound of formula I under item 1 and/or one of its physiologically acceptable salts.

6. The compounds of formula I on p. 1 and their physiologically acceptable salts with inhibitory ability against coagulation factor XA.

7. Drug as an inhibitor of coagulation factor XA, comprising a compound of formula I under item 1 or its physiologically acceptable salt.

 

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in which R1denotes-C(=NH)-NH2which may be substituted once by a group-COA, -CO-[C(R6)2]n-Ar, -COOA, -HE or normal aminosidine group

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R2denotes H, A, OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSО2Ar, COOR6, SOPS(R6)2, CONHAr, COR6, COAr, S(O)nA or S(O)nAr,

R3means And, cycloalkyl, - [C(R6)2]nAr, - [C(R6)2]n-O-Ar, -[C(R6)2]nHet or-C(R6)2=C(R6)2-Ar,

R6denotes H, a or benzyl,

X is absent or represents-CO-, -C(R6)2-, -C(R6)2-C(R6)2-, -C(R6)2-CO-, -C(R6)2-C(R6)2-CO-, -C(R6)= C(R6)-CO-, NR6CO-, -N{[CR6)2]n-COOR6} -CO - or-C(COOR6R6-C(R6)2-CO-,

Y represents-C(R6)2-, -SO2-, -CO-, -COO - or-CONR6-,

And denotes alkyl with 1-20 C-atoms, where one or two CH2-groups can be replaced by O - or S-atom or single, two - or three-fold substituted by the group And, Ah', OR6N(R6)2, NO2CN, Hal, NHCOA, NHCOAr', NHSO2A, NHSО2Ar', COOR6, CON(R6)2, CONHAr', COR6, COAr', S(O)nA or S(O)nAr is phenyl or naphthyl,

AG' refers to unsubstituted or one-, two - or three-fold substituted by a group A, OR6N(R6)2, NO2CN, Hal, NHCOA, COOR6, SOPS(R6)2, COR6or S(0)nA phenyl or naphthyl,

Het denotes a single or dual core unsubstituted or one - or multi-substituted by a group of Hal, A, Ar', COOR6, CN, N(R6)2, NO2, Ar-CONH-CH2and/or carbonyl oxygen saturated or unsaturated heterocyclic ring system containing one, two, three or four identical or different heteroatoms, such as nitrogen, oxygen or sulphur,

Hal denotes F, C1, Br or J,

n denotes 0, 1 or 2,

and their salts

The invention relates to a method for producing 5-hydroxymethyl substituted oxazolidinones formula (III) from the carbamates of the formula (IIA) or trifurcated formula (IIb), using as the starting material dihydroxy compounds of formula (I) or glycidol
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